Lepidinium salts and method of synthesis



Patented Dec. 11, 1951 LEPIDINIUM SALTS AND METHOD OF SYNTHESIS Donald W. Heseltine and Leslie G. S. Brooker, Rochester, N. Y., assignors to Eastman Kodak Company, Rochester, N. Y., a corporation of New Jersey No Drawing.

Application April 8, 1950,

Serial No. 154,882

This invention relates to a new process for preparing lepidinium salts and new quaternary salts obtained thereby.

It is known that lepidine bases can be prepared by reacting an aromatic primary amine hydrochloride with methyl vinyl ketone in the presence of an oxidizing agent, e. g. ferric chloride. (Campbell U. S. Patent 2,451,610, dated October 19, 1948.)

We have now found that acid addition salts of aromatic secondary amines can be condensed with methyl vinyl ketone in the presence of an oxidizing agent to give, not a lepidine base as might be expected, but a lepidinium quaternary salt.

It is, therefore, an object of our invention to provide a new method for preparing lepidinium quaternary salts. A further object is to provide lepidinium salts, some of which have not heretofore been known, Still another object is to provide a method for preparing N-aryl quaternary salts. Other objects will become apparent from a consideration of the following description and examples.

According to our invention we provide a new process for preparing lepidinium quaternary salts which comprises reacting an acid addition salt of an aromatic secondary amine with methyl vinyl ketone in the presence of an oxidizing agent. Y

The aromatic secondary amines whose acid addition salts can be used in our invention comprise the N-alkylarylamines, such as N-methylaniline, N-ethylaniline, N-methyl-p-chloroaniline, N-methyl-p-toluidine, etc., the diarylamines, such as diphenylamine, p,p'-ditolylamine, p,p'- dichlorodiphenylamine, etc. and heterocyclic secondary amines, such as tetrahydroquinoline, dihydroindole (indoline), carbazole, 3,4,5,6-tetra hydrocarbazole, phenothiazine (thiodiphenylamine), phenoxazine (phenazoxine), 2,3-trimethyleneindoline, etc. The acid addition salts of the N-alkylaryl and diaryl amines useful in practicing our invention can advantageously be represented by the following general formula:

wherein R represents an alkyl group, such asmethyl, ethyl, etc., or an aryl group, such as phenyl, o, m-, or p-tolyl, m-, or p-chloro phenyl, o-, m-, or p-hydroxyphenyl, etc. (e; g. a mononuclear aryl group of the benzene series); D represents the non-metallic atoms necessary to complete an aromatic nucleus, such as phenyl,

14 Claims. (01. 26l)286)- nuelear aryl group of the benzene series), and X*represents an acid radical, e. g. chlorine, bromine, iodine, sulfate, chlorate, thiocyanate, alkylsulfate (e. g. methyl sulfate), toluenesulfonata etc. 'I'h'e acid addition salts of the heterocycllc secondary amines useful in practicing our invention can advantageously be represented by the following general formula:

wherein D1 represents the non-metallic atoms necessary to complete an aromatic nucleus, such as phenyl, chlorophenyl, hydroxyphenyl, etc. nuclei (e. g. an aromatic nucleus of the benzene series), X has the meaning given above, and Z represents the non-metallic atoms necessary to complete a heterocyclic nucleus containing from 5 to 6 atoms in the heterocyclic ring, such as tetrahydropyrrole (II represents indoline type), indole (II represents carbazole or tetrahydrocarbazole type), benzothiazine (II represents phenothiazine type), etc. nuclei. The aromatic nuclei can have substituted thereon Cl, Br, al-

koxyl (e. g. methoxyl, etc), hydroxyl, etc. groups, although, as can be seen from the above general formulas, at least one of the positions ortho to the secondary nitrogen atom in the compounds of Formula I,' or peri to that of the secondary nitrogen atom in the compounds of Formula II, should be free of substituents.

:As oxidizing, agents we can advantageously use mononuclear nitroaromatic compounds of the benzene series, such as nitrobenzene, nitrotoluene, etc., nitroaromaticsulfonic acids, such as m-nitrobenzenesulfonic acid, etc., nitrophenols,

such as oand p-nitrophenol, etc., ferric halides, such as ferric chloride, etc., arsenic pentoxide or arsenic acid, etc. Ordinary air can be used in the absence of an oxidizing agent, although less advantageously than in the presence of the conventional oxidizing agents set out above.

Instead of employing the acid addition salt of.

the secondary amine as such, according to the method described above and in certain of the tion salt with the secondary amine, and the latter o-, m-, and p-chlorophenyl, etc. (e. g. a mono-" undergoes condensation with the ketone. Hydrochloric or sulfuric acids have been found to provide aqueous solutions which are excellently adapted as reaction media for the process of our invention. A. condensation agent or. catalyst. such as zinc chloride, etc; can be; added to the reaction mixtures, if desired. The condensation agent can also serve as an oxidizing agent, or. can be used with an oxidizing agent, such as ferric chloride.

The reaction can be carried out at room temperature (about 25 C.) or at temperatures. as high as the refluxing temperature of the. reactants. Generally, heating the reactantsv at refiuxing temperature provides a rapid, efficient process. alcohols, 1,ldioxane, etc., can be employed. if: desired.

The process of our invention can be carried out in stepwise fashion by first condensing the aromatic. secondary amine addition salt withthe.

are those represented by the following two general formulas:

III

CH (11H /L N Zl X wherein Dlhas the value set forth above, R1; represents a mono-nuclear aromatic nucleus of the benzene series (e. g. phenyl, oand p-chloro phenyl, oand p-methoxyphenyl, etc.), Z1. represents the non-metallic atoms necessary to complete a heterocyclic nucleus containing: from 5 to 6 atoms in the heterocyclic ring, and, X has the value set forth above. Among the compounds. coming within the scope of Formula IV are those represented by the following three general formulas'z V CB;

Inert diluents, e. g. aliphatic primary,

wherein D1; and X have the values set forth above, Dz represents a carbocyclic nucleus containing from 5' to 6. atoms in the ring, and 01, represents a positive integer from 2 to 3.

The following examples will serve to illustrate further; the manner whereby we practice our invention.

Example 1.1-phenyllepidinium iodide Diphenylamine hydrochloride (102.5 g.), o-nitrophenol (.46. g.), and anhydrous zinc chloride. (5 g.) were dissolved in 4100. cc. absolute ethyl alcohol. The. reaction mixture. was heated under reflux with mechanical stirring and 50 g. of methylvinyl ketone were added. dropwise over a period ofv two hours. The heatingv was continued overnight and then. the alcohol was. removed, and the residue extracted with two liters of boiling water. The aqueous portion was then made just alkaline with alkali, treated with decolorizing carbon and filtered. The filtrate was acidified with hydrochloric acid, 50 g. of sodium iodide added and the solution evaporated to dryness under reduced pressure. The dry salts were then extracted with two'300 cc. portions of absolute ethyl alcohol and the alcohol extracts concentrated to cc. and chilled overnight. The quaternary salt was filtered off and recrystallized from 150 cc. of water yielding 30.5 g. (17%) of amber colored crystals with aM. P. of 233-235 C. with decomposition.

Anal. calcd. for CIGHMINI I, 36,6. Found: I, 36.40..

Example 2.1,8-trimethylenelepidinium iodide Tetrahydroquinoline hydrochloride (60 g.), ferric chloride (anhydrous) g.) and anhydrous zinc chloride (5 g.) were dissolved in 300 cc. of absolute ethyl alcohol. The reaction mixture was heated under reflux with mechanical stirring and 38 g. of methylvinyl ketone were added dropwise over a period of two hours. The reaction mixture was refluxed overnight and the alcohol distilled off. The residue was extracted with three liters of' boiling water and the Water solution made just alkaline with 40% sodium hydroxide. Filter-eel (100 g.) was added, the

solution filtered, and the filtrate acidified with hydrochloric acid. Then 50 g. of sodium iodide were added and the aqueous solution was taken to dryness under reduced pressure. The mixture of salts was extracted with 500 cc. of boiling absolute ethyl alcohol, the alcohol solution concentratedto 150 cc., and chilled overnight. The quaternary salt was filtered off, dissolved in a minimum amount of boiling water, treated with 2 g. of decolorizing carbon, filtered and chilled. The product was filtered off and dried, yielding 22 g. (19.4%) of yellow crystals having a M. P. of 186-l87 C. with decomposition.

Anal. calcd. for C13H14INZ I, 40.8. Found: I, 41.0.

Example 3.--1,8-ethylenelepidinium iodide mixture was heated overnight and then the alcohol distilled off on the steam bath. The residue was extracted with three liters of boiling water, the aqueous solution filtered, treated with decolorizing carbon and made just alkaline with sodium hydroxide. Filter-eel (100 g.) was stirred in, the solution filtered, made just acid with hydrochloric acid and g. of sodium iodide added. The aqueous solution was then evaporated to dryness under reduced pressure and the combined salts were extracted with two 300 cc. portions of absolute ethyl alcohol. The alcoholic extracts were concentrated to 150 cc. and chilled overnight. The crystalline quaternary salt was filtered off and recrystallized from 100 cc. of water yielding 23.8 g. (17%) of yellowish crystals having a M. P. of 192-194" C. with decomposition.

Anal. calcd. for C12H12IN2 I, 42.7." Found: I, 42.6.

Example 4.-1,S-O-phenyZeneZepidinium iodide C'arbazole (84 g.) was suspended in 400 cc. of absolute ethyl alcohol and 49 g. of sulfuric acid was added dropwise with stirring. Then 23 g. of o-nitrophenol and 10 g. of anhydrous zinc chloride were added and the reaction mixture heated to reflux temperature. Methylvinyl ketone (50 g.) was then added dropwise over a period of two hours and the heating continued overnight. The alcohol was removed by distillation, the residue extracted with four litersof boiling water, and the aqueous extract neutralized with sodium carbonate. The water solution was treated with decolorizing carbon,-

6 filtered, acidified with hydrochloric acid, 20 g. of sodium iodide added, and then evaporated to dryness under reduced pressure. The dry mixed salts were extracted with 500 cc. of absolute alcohol. The alcoholic solution was concentrated to 75 cc. and the quaternary salt thrown out of solution by the addition of ether. The ether-alcohol solution was decanted and the sticky residue stirred with acetone until crystalline. The quaternary salt was filtered off and recrystallized from ethyl alcohol yielding 6.2 g.

(3.6%) of yellowish powder.

3,4,5,6-tetrahydrocarbazole (85.6 g.) was dissolved in 500 cc. of nitrobenzene in a two-liter,

three-necked flask fitted with a condenser and a mechanical stirrer. Concentrated surfuric acid (49 g.) was added dropwise,the reaction mixture was heated to the reflux temperature and 70 g. of methylvinyl ketone were added dropwise over a period of one hour. The heating and stirring were continued overnight and then the nitrobenzene was removed by steam distillation. The aqueous solution was decanted from the tar, neutralized with sodium carbonate, extracted with benzene, and finally, acidified with hydrochloric acid. The aqueous portion was then evaporated to dryness under reduced pressure and the mixed salts remaining were extracted with 500 cc. of absolute ethyl alcohol. The alcoholic solution was concentrated to m1., chilled, and filtered. The crude quaternary salt was dissolved in 100 cc. of hot water and precipitated by the addi tion of 10 g. of sodium iodide yielding 9.5 g. (5%) of brown powder. Recrystallization from water gave yellow cubes, M. P. 268-270 C. with decomposition.

Example 6.-1,8-o-cyclopentylenelepidinium perchlorate ascsgsoac.

residue was extracted with one. liter of boiling: water and the aqueous portion; neutralized with.

sodium carbonate and: extracted withsbenzene. The aqueous extract was then acidifiedwith hy'- drochloric acid and concentrated'to 100 cc. The crude quaternary salt was precipitated by the addition of sodium perchlorate (20 g. in 40 cc. of

water), the solution chilled and the water decanted leaving 25 g. (41%) of crude product as a heavy yellow oil. The salt, after repeated washing with water, ether and ethyl alcohol and drying for 48 hours over calcium chloride in a vacuum desiccator, was a yellow, friable, very hygroscopic solid.

The 1, 2, 3, 4, 3a, 8b-hexahydrocyclopentindole used in the above example was prepared by reducing l, 2, 3, e,-tetrahydrocyclopentindole in an alcoholic solution using Raney nickel as a catalyst. The solution was heated at 100 C. for 24 hours at 1500 p. s. i. The: desired product was obtained as a colorless liquid boiling at 98 100 C./10 mm.

Earample 7.-3methylpyrido-(k, Z) mhenothiazinium iodide Phenothiazine (199 g.) was suspended in one liter of absolute ethyl alcohol and o-nitrophenol.

(46 g.) and anhydrous zinc chloride g.) were added. Concentrated-sulfuric acid (98 g.)- was added dropwise with stirring. The reaction mixture was then heated to boiling in a five-liter, three-necked flask fitted with a condenser and a mechanical stirrer and methyl vinyl ketone (freshly distilled) (80 g.) was added dropwise over a period of two hours. The reaction-mixture was heated under reflux overnight and then as much alcohol as possible removed by distillation. The residue was stirred with several portions of ether and the ether decanted. The remaining oil was stirred with three liters of acetone to remove the excess phenothiazine. The acetone was decanted and the residue extracted with one liter of boiling water. The aqueous extract was treated with decolorizing carbon, filtered and sodium iodide (20 g.) added and the solution chilled. The product was filtered on, washed with acetone and recrystallized from methyl alcohol and then from water, yielding 7.3 g. (2%) of amber crystals melting at 287-288 C. with decomposition.

Operating in a manner similar to that illustrated above, other lepidinium salts can be prepared. according to the process of our invention. The lepidinium salts prepared according to the process of our invention can be used in the preparation of other useful materials, such as polymethine dyes, as described in the application of Donald W. Heseltine and Lesile G. S. Brooker, Serial No. 154,883, filed on even date herewith.

What we claim. as our invention and desire secured by Letters Patent of the United States is:

l. A process for preparing lepidinium quaternary salts comprising'condensing a compound se- 8: lected from those represented by th f n m generalformula:

D1 represents the non-metallic atoms necessary to complete an aromatic nucleus, Z represents the non-metallic atoms necessary tocomplete a heterocyclic nucleus containing from 5 to 6 atoms in the heterocyclic ring, and X represents an acid radical, with methyl vinyl ketone in the presence of an oxidizing agent.

2. A process for preparing lepidinium quaternary salts comprisingcondensing a compound selected from those represented by the following general formula:

wherein D1 represents the non-metallic atoms necessary to complete a mononuclear aryl group of the benzene series, Z represents the non-metallic atoms necessary to complete a heterocyclic nucleuscontaining from 5 to6 atoms in the heterocyolic ring, and X represents an acid radical, with methyl vinylketone in the presence of an oxidizing agent;

3. A process-for preparing lepidinium quaternary salts comprising condensing a compound selected from those represented by the following general formula:

o H wherein D1 represents the non-metallic atoms necessary to complete a mononuclear aryl group of the benzene series, Z represents the non-metallic atoms necessary to complete a heterccyolic nucleus containing from 5 to 6 atoms in the heterocyclic ring, and X represents an acid radical, with methyl vinyl ketone in the presence of a ferric halide.

5. A process for preparing lepidinium quaternary'salts comprisingcondensinga compound selected from those represented by the following general formula:

wherein Z represents the non-metallic atoms necessary to complete a heterocyclic nucleus containing from to 6 atoms in the heterocyclic ring, with methyl vinyl ketone in the presence of a mononuclear nitroaromatic compound of the benzene series.

6. A process for preparing lepidinium quaternary salts comprising condensing a compound selected from those represented by the following general formula:

wherein Z represents the non-metallic atoms necessary to complete a heterocyclic nucleus containing from 5 to 6 atoms in the heterocyclic ring, with methyl vinyl ketone in the presence of a ferric halide.

'7. The lepidinium quaternary salts selected from those represented by the following general formula:

wherein D1 represents the non-metallic atoms necessary to complete a mononuclear aryl group of the benzene series, Z1 represents the non-metallic atoms necessary to complete a heterocyclic nucleus containing from 5 to 6 atoms in the heterocyclic ring, and X represents an acid radical.

8. The lepidinium quaternary salts selected from those represented by the following general formula:

wherein D1 represents the non-metallic atoms necessary to complete a mononuclear aryl group of the benzene series, X represents an acid radical, and n represents a positive integer from 2 to 3.

9. The lepidinium quaternary salts selected from those represented by the following general formula:

wherein D1 represents the non-metallic atoms necessary to complete a monocyclic aryl group of the benzene series, D2 represents the non-metallic atoms necessary to complete a carbocyclic nucleus containing 6 atoms in the ring, and X represents an acid radical.

10. The lepidinium quaternary salts selected from those represented by the following general 5 formula:

wherein D1 represents the non-metallic atoms necessary to complete a mononuclear aryl group of the benzene series, D2 represents the non-me-- tallic atoms necessary to complete a carbocyclic nucleus containing 5 atoms in the rings.

13. The lepidinium quaternary salt represented by the following formula:

14. The lepidinium quaternary salt represented by the following formula:

DONALD W. HESELTINE. LESLIE G. S. BROOKER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,158,287 Konig May 16, 1939 15 2,265,908 Kendall Dec. 9, 1941 

7. THE LEPIDINUM QUATERNARY SALTS SELECTED FROM THOSE REPRESENTED BY THE FOLLOWING GENERAL FORMULA: 